Use of newer anticonvulsants for the treatment of status epilepticus.

Farrokh S, Erdman M, Bon J, Tesoro E. Use of Newer Anticonvulsants for the Treatment of Status Epilepticus. Pharmacotherapy. 2019 Feb 5. doi:10.1002/phar.2229. [Epub ahead of print]

Abstract

Status Epilepticus (SE) has a high mortality rate and is one of the most common neurological emergencies. Fast progression of this neurological emergency and lack of response to traditional antiepileptic drugs (AEDs) in most cases has challenged clinicians to use new agents. The objective of this paper was to evaluate the efficacy and safety of AEDs released to the market after 2000 for SE, refractory SE (RSE), and super refractory SE (SRSE). The PubMed database was searched for clinical trials published between January 2000 and July 2018 using the search terms status epilepticus, refractory status epilepticus, super refractory status epilepticus, brivaracetam, clobazam, cannabidiol, eslicarbazepine, lacosamide, perampanel, rufinamide, stiripentol, and zonisamide. Trials that evaluated these agents in adults with SE, RSE, and SRSE were included. Brivaracetam use was identified in two retrospective reviews with success rates of 27% and 57%. One unsuccessful case report of cannabidiol use in SE was found. Four clobazam studies were identified in SE and RSE with success rate ranging from 25% to 100%. No evidence for the use of eslicarbazepine and zonisamide was found. Using the search terms for lacosamide identified 38 articles; one systematic review, five prospective studies, 15 retrospective reviews, and 17 case reports. Success rates and dosing varied, but studies that included focal or partial types of SE showed higher success rates. Five articles were identified regarding perampanel use in this setting. Three were retrospective reviews with success rates ranging from 17% to 60%, and two were case reports. Only one case report regarding the use of rufinamide was found; rufinamide titrated up to 4.4 mg/day allowed discontinuation of barbiturate and clobazam. One case report and two case series of stiripentol were found with reported efficacy between 60-100% in SRSE. Currently, there is insufficient evidence to support the use of these agents in this setting.

Santamarina E, González-Cuevas M, Toledo M, Jiménez M, Becerra JL, Quílez A, Suller A, Mauri JA, Fernández Á, Marinas A, Quintana M, Puig XS. Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy.Epilepsy Behav. 2018 Jul;84:93-98.

Abstract

BACKGROUND:

Some studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated.

OBJECTIVE:

The objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE.

METHODS:

A group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected.

RESULTS:

One hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ± 17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100-600 mg), and the weight-adjusted dose was 5 mg/kg (3-6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h. Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found.

CONCLUSIONS:

In adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.

From the article:

The median loading dose used was 400 mg (100–600 mg), and the weight-adjusted dose was 5 mg/kg (3–6 mg/kg). If we observe the dose distribution, most patients received between 200 and 400 mg of total dose and between 4 and 6 mg/kg when adjusted by weight…

Regarding safety, 16 patients had adverse effects attributed to LCM. These were of mild intensity in 14 (increased drowsiness in 9, diplopia in 2, vomiting in 1, blurred vision in 1, and increase in PR interval in 1) and more severe cardiac complications in 2: hypotension and bradycardia in 1 patient, and atrioventricular (AV) block in the other…

On the other hand, this is a retrospective analysis, and we have not been able to define the upper limit of the loading dose. Taking into account the study by Ramsay et al., we can assume that it should not exceed 12 mg/kg; however, prospective studies or clinical trials would be needed to validate the benefit of increasing the loading dose and not exposing patients to a risk of overexposure.